Manufacturing of eye preparations.

One of the major problems encountered with topical administration is the rapid precorneal loss caused by nasolacrimal drainage and high tear fl uid turnover, which leads to drug concentrations of typically less than 10% of the applied drug.

Approaches to improve the ocular bioavailability have been attempted in two directions: to increase the corneal permeability by using penetrations enhancers or prodrugs and to prolong the contact time with the ocular surface by using viscosity - enhancing or in situ gelling polymers

Conventional dosage forms such as solutions, suspensions, and ointments account for almost 90% of the currently accessible ophthalmic formulations on the market. They offer some advantages such as their ease of administration by the patient, ease of preparation, and the low production costs. However, there are also signifi cant disadvantages associated with the use of conventional solutions in particular, including the very short contact time with the ocular surface and the fast nasolacrimal drainage, both leading to a poor bioavailability of the drug.

Various ophthalmic delivery systems have been investigated to increase the corneal permeability and prolong the contact time with the ocular surface. However, conventional eye drops prepared and administered as aqueous solutions remain the most commonly used dosage form in ocular disease management.

Solutions

The reasons behind choosing solutions over other dosage forms are their favorable cost advantage, the simplicity of formulation development and production, and the high acceptance by patients. However, there are also a few drawbacks, such as rapid and extensive precorneal loss, high absorption via the conjunctiva and the nasolacrimal duct leading to systemic side effects, as well as the increased installation frequency resulting in low patient compliance.

Some of these problems have been encountered by addition of viscosity - enhancing agents such as cellulose derivates, which are believed to increase the viscosity of the preparation and consequently reduce the drainage rate. The use of viscosity enhancers will be discussed later in this section.

Suspensions

Suspensions of the micronized drug ( < 10 μ m) in a suitable aqueous vehicle are formulated, where the active compound is water insoluble. This is the case for most of the steroids. It is assumed that the drug particles remain in the conjunctival sac, thus promoting a sustained release effect. There have been many studies trying to prove this assumption, but none of them has revealed a pronounced prolonged release profi le.

According to Davies, topical ophthalmic suspensions have a number of limitations compared to solutions. They need to be adequately shaken before use to ensure correct dosing, a process which can result in poor patient compliance. In addition, they need to be sterilized, which may cause physical instability of the formulation.

Furthermore, the amount of drug required to achieve only a moderate increase in bioavailability is very high, rendering suspensions expensive in terms of their production costs.

The drug particle size plays the most important role in the formulation process of suspensions. Particles greater than 10 μ m cause patient discomfort. As they are perceived as foreign substances, they cause refl ex tearing in order to eliminate the particles from the ocular surface. A study by Schoenwald and Stewart showed the infl uence of the particle size of dexamethasone on its bioavailability.a

The in vivo dissolution rate decreased with increasing particle size to the point when particles were removed from the conjunctival sac before the dissolution was complete.

As a result, achieving a near - solution state with small particles that are easy to resuspend and show minimal sedimentation remains the goal when formulation of a suspension is unavoidable.

Ointments

Ointments generally consist of a dissolved or dispersed drug in an appropriate vehicle base. They are the most commonly used semisolid preparations as they are well tolerated and fairly safe and increase the ocular bioavailability of the drug. The instilled ointment breaks up into small oily droplets that remain in the cul - de - sac as a drug depot. The drug eventually gets to the ointment – tear interface due to the shearing action of the eyelids.

Sieg and Robinson compared the bioavailability of fl uorometholone in a solution, a suspension, and an ointment. They found that the peak concentration (cmax ) of the drug in the aqueous humor of rabbits was comparable with all three formulations, whereas the time to peak concentration ( tmax ) occurred much later with the ointment, leading to a signifi cantly greater total bioavailability of the drug.

Overall, ophthalmic ointments offer the following advantages: reduced dilution of the medication via the tear fi lm, resistance to nasolacrimal drainage, and an increased precorneal contact time. However, oily viscous preparations for ophthalmic use (such as ointments) can cause blurred vision and matting of the eyelids and may also be associated with discomfort by the patient as well as occasional ocular mucosal irritation. Ointments are therefore generally used in combination with eye drops, which can be administered during the day, while the ointment is applied at night, when clear vision is not required.

Polymeric systems used for ocular drug delivery can be divided into three groups: viscosity - enhancing polymers, which simply increase the formulation viscosity, resulting in decreased lacrimal drainage and enhanced bioavailability; mucoadhesive polymers, which interact with the ocular mucin, therefore increasing the contact time with the ocular tissues; and in situ gelling polymers, which undergo sol - to – gel phase transition upon exposure to the physiological conditions present in the eye.

Viscosity -Enhancing Polymers

In order to reduce the lacrimal clearance (drainage) of ophthalmic solutions, various polymers have been added to increase the viscosity of conventional eye drops, prolong precorneal contact time, and subsequently improve ocular bioavailability of the drug. Among the range of hydrophilic polymers investigated in the area of ocular drug delivery are polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP), cellulose derivates such as methylcellulose (MC), and polyacrylic acids (carbopols).

Chrai and Robinson evaluated the use of an MC solution of pilocarpine in albino rabbits and found a decrease in the drainage rate with increasing viscosity.

Patton and Robinson investigated the relationship between the viscosity and the contact time or drainage rate and demonstrated an optimum viscosity of 12 – 15 cps for an MC solution in rabbits. The infl uence of different polymers on the activity of pilocarpine in rabbits and human was reported by Saettone et al.

The ocular shear rate ranges from 0.03 s − 1 during interblinking periods to 4250 – 28,500 s − 1 during blinking. It has a great infl uence on the rheological properties of viscous ocular dosage forms and consequently the bioavailability of the incorporated drug. Newtonian systems do not show any real improvement of bioavailability below a certain viscosity and blinking becomes painful, followed by refl ex tearing, if the viscosity is too high. While the viscosity of Newtonian systems is independent from the shear rate, non - Newtonian pseudoplastic or so – called shear - thinning systems exhibit a decrease in viscosity with increasing shear rates.

Mucoadhesive Polymers

Bioadhesion refers to the attachment of a drug molecule or a delivery system to a specifi c biological tissue by means of interfacial forces. If the surface of the tissue is covered by a mucin fi lm, as is the case for the external globe, it is more commonly referred to as mucoadhesion.

In order to be an effective mucoadhesive excipient, polymers must show one or more of the following features: strong hydrogen binding group, strong anionic charge, high molecular weight, suffi cient chain fl exibility, surface energy properties favoring spreading onto the mucus, and near - zero contact angle to allow maximum contact with the mucin coat.

The most commonly used bioadhesives are macromolecular hydrocolloids with numerous hydrophilic functional groups capable of forming hydrogen bonds (such as carboxyl, hydroxyl, amide, and sulfate groups). Hui and Robinson were the fi rst to demonstrate the usefulness of bioadhesive polymers in improving the ocular bioavailability of progesterone. Saettone et al. evaluated a series of bioadhesive dosage forms for ocular delivery of pilocarpine and tropicamide and found hyaluronic acid to be the most promising mucoadhesive polymer.

Lehr et al. suggested that cationic polymers, which are able to interact with the negative sialic acid residues of the mucin, would probably show better mucoadhesive properties than anionic or neutral polymers. They investigated the polycationic polymer chitosan and demonstrated that the mucoadhesive performance of chitosan was signifi cantly higher in neutral or slightly alkaline pH as it is present in the tear fl uid.a

However, according to Park and Robinson, polyanions are better than polycations in terms of binding and potential toxicity. In general, both anionic and cationic charged polymers demonstrate better mucoadhesive properties than nonionic polymer, such as cellulose derivates or PVA.a

The mechanism of mucoadhesion involves a series of different steps. First, the mucoadhesive formulation needs to establish an intimate contact with the corneal surface. Prerequisites are either good wetting or swelling of the mucoadhesive polymer as well as suffi cient spreading across the cornea.

The second stage involves the penetration of the mucoadhesive polymer chains into the crevices of the tissue surface and also the entanglement with the mucous chains. On a molecular level, mucoadhesion is a results of van - der - Waals forces, electrostatic attractions, hydrogen bonding, and hydrophobic interactions.

Mucoadhesive polymers increase the contact time of a formulation with the tear fi lm and simulate the continuous delivery of tears due to a high water – restraining capacity. As such, they allow a decrease in the instillation frequency compared to common eye drops and are therefore useful as artifi cial tear products.

In Situ Gelling Systems

In situ gelling systems are viscous polymer - based liquids that exhibit sol - to - gel phase transition on the ocular surface due to change in a specifi c physicochemical parameter (ionic strength, temperature, pH, or solvent exchange). They are highly advantageous over preformed gels as they can easily be instilled in liquid form but are capable of prolonging the residence time of the formulation on the surface of the eye due to gelling.

The principal advantage of in situ gelling systems is the easy, accurate, and reproducible administration of a dose compared to the application of preformed gels.

The concept of forming gels in situ (e.g., in the cul - de - sac of the eye) was fi rst suggested in the early 1980s, and ever since then various triggers of in situ gelling have been further investigated.

Polymers that may undergo sol - to - gel transition triggered by a change in pH are cellulose acetate phthalate (CAP) and cross - linked polyacrylic acid derivates such as carbopols, methacrylates and polycarbophils. CAP latex is a free - running solution at pH 4.4 which undergoes sol - to - gel transition when the pH is raised to that of the tear fl uid.

This is due to neutralization of the acid groups contained in the polymer chains, which leads to a massive swelling of the particles. The use of pH – sensitive latex nanoparticles has been described by Gurny et al. Carbopols have apparent p Ka values in the range of 4 – 5 resulting in rapid gelation due to rise in pH after ocular administration.

Gellan gum is an anionic polysaccharide which undergoes phase transition under the infl uence of an increased ionic strength. In fact, the gel strength increases proportionally with the amount of mono - or divalent cations present in the tear fl uid.

As a consequence, the usual refl ex tearing, which leads to a

dilution of common viscous solutions, further enhances the viscosity of gellan gum formulations due to the increased amount of tear fl uid and thus higher cation concentration.

Shedden et al compared the plasma concentrations of timolol following multiple applications of Timoptic - XE and a timolol maleate solution. They found that a once - daily application of the in situ gelling formulation was suffi cient to reduce the intraocular pressure to levels comparable to a twice - daily application of the solution, leading to better patient compliance as well as a reduction in systemic side effects.

Poloxamers or pluronics are block copolymers consisting of poly(oxyethylene) and poly(oxypropylene) units. They rapidly undergo thermal gelation when the temperature is raised to that of the ocaular surface (32 ° C), while they remain liquid at refrigerator temperature. Poloxamers exhibit surface active properties, but even if used in high concentrations (usually between 20 and 30%), Pluronic F127 was found no more damaging to the cornea than a physiological saline solution.

In order to reduce the total polymer concentration and achieve better gelling properties, several poloxamer combinations have been tested. Wei et al used a mixture of Pluronic F127 and F68 resulting in a more suitable phase transition temperature with a free - fl owing liquid under 25 ° C.

Combining thermal - with pH - dependent gelation, Kumar et al. developed a combination of methylcellulose 15% and carbopol 0.3%.

This composition exhibited a sol - to - gel transition between 25 and 37 ° C with a pH increase from 4 to 7.4. A possible mechanism for the thermal effect could be the decrease in the degree of the methylcellulose hydration, while the polyacrylic acid can transform into a gel upon an increase in pH due to the buffering properties of the tear fl uid.

Colloidal carriers have been investigated as drug delivery systems for the past 30 years in order to achieve specifi c drug targeting, facilitate the bioavailability of drugs through biological membranes, and protect the drug against enzymatic degradation.

Their use in topical administration and especially in ocular delivery however has only been studied for the last two decades.

Colloidal carriers are small particulate systems ranging in size from 100 to 400 nm.

As they are usually suspended in an aqueous solution, they can easily be administered as eye drops, thus avoiding the potential discomfort resulting from bigger particles present in ocular suspensions or from viscous or sticky preparations.

Most efforts in ophthalmic drug delivery have been made with the aim of increasing the corneal penetration of the drug. Calvo et al. have shown that colloidal particles are preferably taken up by the corneal epithelium via endocytosis. It has also been stated by Lallemand and co - workers , that the cornea acts as a drug reservoir, slowly releasing the active compound present in the colloidal delivery system to the surrounding ocular tissues.

Nanoparticles

Nanoparticles have been among the most widely studied particulate delivery systems over the past three decades. They are defi ned as submicrometer - sized polymeric colloidal particles ranging from 10 to 1000 nm in which the drug can be dissolved, entrapped, encapsulated, or adsorbed.

Depending on the preparation process, nanospheres or nanocapsules can be obtained. Nanospheres have a matrixlike structure where the drug can either be fi rmly adsorbed at the surface of the particle or be dispersed/dissolved in the matrix. Nanocapsules, on the other hand, consist of a polymer shell and a core, where the drug can either be dissolved in the inner core or be adsorbed onto the surface.a

The fi rst nanoparticulate delivery system studied was Piloplex, consisting of pilocarpine ionically bound to poly(methyl)methacrylate – acrylic acid copolymer nanoparticles. Klein et al. found that a twice - daily application of Piloplex in glaucoma patients was just as effective as three to six instillations of conventional pilocarpine eye drops. However, the formulation was never accepted for commercialization due to various formulation - related problems, including the nonbiodegradability, local toxicity, and diffi culty of preparing a sterile formulation.

Another early attempt to formulate a nanoparticulate system for the delivery of pilocarpine was made by Gurny. This formulation was based on pilocarpine dispersed in a hydrogen CAP pseudolatex formulation. Gurny and co - workers compared the formed nanoparticles to a 0.125% solution of hyaluronic acid some years after their fi rst investigation and found that the viscous hyaluronic acid system showed a signifi cantly longer retention time in front of the eye than the pseudolatex formulation.

The most commonly used biodegradable polymers in the preparation of nanoparticulate systems for ocular drug delivery are poly - alkylcyanoacrylates, poly - ε - caprolactone, and polylactic - co - glycolic acid copolymers. Marchal - Heussler et al. compared the three particulate delivery systems using antiglaucoma drugs including betaxolol and cartechol. Results showed that poly - ε - caprolactone (nanospheres and nanocapsules) exhibited the highest pharmacological activity when loaded with betaxolol.

It seemed that the higher ocular activity was related to the hydrophobic nature of the carrier and that the mechanism of action seemed to be directly linked to the agglomeration of the particles in the conjunctival sac. In general, nanocapsules displayed a much better effect than nanospheres probably due to the fact that the active compound was in its un - ionized form in the oily core and could diffuse faster into the cornea. Diffusion of the drug from the oily core of the nanocapsule to the corneal epithelium seems to be more effective than diffusion from the internal, more hydrophilic matrix of the nanospheres.

In order to achieve a sustained drug release and a prolonged therapeutic activity, nanoparticles must be retained in the cul - de - sac and the entrapped drug must be released from the particles at a certain rate. If the release is too fast, there is no sustained release effect. If it is too slow, the concentration of the drug in the tears might be too low to achieve penetration into the ocular tissues. The major limiting issues for the development of nanoparticles include the control of particle size and drug release rate as well as the formulation stability.

So far, there is only one microparticulate ocular delivery system on the market. Betoptic S is obtained by binding of betaxolol to ion exchange resin particles. Betoptic S 0.25% was found to be bioequivalent to the Betoptic 0.5% solution in lowering the intraocular pressure.

Liposomes

Liposomes were fi rst reported by Bangham in the 1960s and have been investigated as drug delivery systems for various routes ever since then. They offer some promising features for ophthalmic drug delivery as they can be administered as eye drops but will localize and maintain the pharmacological activity of the drug at its site of action. Due to the nature of the lipids used, conventional liposomes are completely biodegradable, biocompatible, and relatively nontoxic.

A liposome or so - called vesicle consists of one or more concentric spheres of lipid bilayers separated by water compartments with a diameter ranging from 80 nm to 100 μ m. Owing to their amphiphilic nature, liposomes can accommodate both lipohilic (in the lipid bilayer) and hydrophilic (encapsulated in the central aqueous compartment) drugs.

According to their size, liposomes are classifi ed as either small unilamellar vesicles (SUVs) (10 – 100 nm) or large unilamellar vesicles (LUVs) (100 – 300 nm). If more than one bilayer is present, they are referred to as multilamellar vesicles (MLVs). Depending on their lipid composition, they can have a positive, negative, or neutral surface charge.

Liposomes are potentially valuable as ocular drug delivery systems due to their simplicity of preparation and versatility in physical characteristics. However, their use is limited by instability (due to hydrolysis of the phospholipids), limited drug - loading capacity, technical diffi culties in obtaining sterile preparations, and blurred vision due to their size and opacity.

In addition, liposomes are subject to the same rapid precorneal clearance as conventional ocular solutions, especially the ones with a negative or no surface charge. Positively charged liposomes, on the other hand, were reported to exhibit a prolonged precorneal retention due to electrostatic interactions with the negative sialic acid residues of the mucin layer .

There have been several attempts to use liposomes in combination with other newer formulation approaches, such as incorporating them into mucoadhesive gels or coating them with mucoadhesive polymers. Mucoadhesive polymers inves- tigated in this regard were poly(acrylic acid) (PAA), hyaluronic acid (HA), chitosan, and poloxamer.

Durrani and co - workers reported on the infl uence of a carbopol coating on the corneal retention of pilocarpine - loaded liposomes, and demonstrated a biphasic response with an initial low intensity followed by a sustained reaction.

Bochot et al. developed a novel delivery system for oligonucleotides by incorporating them into liposomes and then dispersing them into a thermosensitive gel composed of poloxamer 407. They compared the in vitro release of the model oligonucleotides pdT16 from simple poloxamer gels (20 and 27% poloxamer) with the ones where pdT16 was encapsulated into liposomes and then dispersed within the gels.

They found that the release of the oligonucleotides from the gels was controlled by the poloxamer dissolution, whereas the dispersion of liposomes within 27% poloxamer gel was shown to slow down the diffusion of pdT16 out of the gel.

Niosomes

In order to circumvent some of the limitations encountered with liposomes, such as their chemical instability, the cost and purity of the natural phospholipids, and oxidative degradation of the phospholipids, niosomes have been developed. Niosomes are nonionic surfactant vesicles which exhibit the same bilayered structures as liposomes. Their advantages over liposomes include improved chemical stability and low production costs. Moreover, niosomes are biocompatible, biodegradable, and nonimmunogenic.

They were also shown to increase the ocular bioavailability of hydrophilic drugs signifi cantly more than liposomes. This is due to the fact that the surfactants in the niosomes act as penetrations enhancers and remove the mucous layer from the ocular surface.

A modifi ed version of niosomes are the so - called

discomes, which vary from the conventional niosomes in size and shape. The larger size of the vesicles (12 – 60 μ m) prevents their drainage into the nasolacrimal drainage system. Furthermore, their disclike shape provides them with a better fi t in the cul - de - sac of the eye.

Vyas et al. demonstrated that discomes entrapped higher amounts of timolol maleate than niosomes and that both niosomes and discomes signifi cantly increased the bioavailability of timolol maleate when compared to a conventional timolol maleate solution.

Microemulsions

Microemulsions (MEs) are colloidal dispersions composed of an oil phase, an aqueous phase, and one or more surfactants. They are optically isotropic and thermodynamically stable and appear as transparent liquids as the droplet size of the dispersed phase is less than 150 nm. One of their main advantages is their ability to increase the solubilization of lipophilic and hydrophilic drugs accompanied by a decrease in systemic absorption.

Moreover, MEs are transparent systems thus enable monitoring of phase separation and/or precipitation. In addition, MEs possess low surface tension and therefore exhibit good wetting and spreading properties.

While the presence of surfactants is advantageous due to an increase in cellular membrane permeability, which facilitates drug absorption and bioavailability, caution needs to be taken in relation to the amount of surfactant incorporated, as high concentrations can lead to ocular toxicity.

In general, nonionic surfactants are preferred over ionic ones, which are generally too toxic to be used in ophthalmic formulations. Surfactants most frequently utilized for the preparation of MEs are poloxamers, polysorbates, and polyethylene glycol derivatives.

Similar to all other colloidal delivery systems discussed above it was hypothesized by numerous research teams that a positive charge (provided by cationic surfactants ) would increase the ocular residence time of the formulation due to electrostatic interactions with the negatively charged mucin residues. However, toxicological studies contradicted this assumption regarding the ocular effects, and so far there has been no publication demonstrating a distinct benefi cial effect of charged surfactants incorporated into MEs.

Microemulsions can be classifi ed into three different types depending on their microstructure: oil - in - water (o/w ME), water - in - oil (w/o ME), and bicontinuous ME.

They have been investigated by physical chemists since the

1940s but have only gained attention as potential ocular drug delivery carriers within the last two decades.

Gasco and co - workers investigated the potential

application of o/w lecithin

MEs for ocular administration of timolol, in which the drug was present as an ion pair with octanoate. The ocular bioavailability of the timolol ion pair incorporated into the ME was compared to that of an ion pair solution as well as a simple timolol solution. Areas under the curve for the ME and the ion pair solution respectively were 3.5 and 4.2 times higher than that of the simple timolol solution. A prolonged absorption was achieved using the ME with detectable amounts of the drug still present 120 min after instillation.

Various lecithin - based MEs were also characterized by Hasse and Keipert.

The formulations were tested in terms of their

physicochemical parameters (pH, refractive index, osmolality, viscosity, and surface tension) and physiological compatibility (HET - CAM and Draize test). In addition, in vitro and in vivo evaluations were performed. The tested MEs showed favorable physicochemical parameters and no ocular irritation as well as a prolonged pilocarpine release in vitro and in vivo.

Muchtar and co - workers prepared MEs with poloxamer 188 and soybean lecithin to deliver indometacin to the ocular tissues. They found a threefold increased indomethacin concentration in the cornea and aqueous humor 1 h post - instillation.

Beilin et al. demonstrated a prolonged ocular retention of a submicrometer emulsion (SME) in the conjunctival sac using a fl uorescent marker (0.01% calcein) as well as the miotic response of New Zealand Albino rabbits to pilocarpine. They found that the fl uorescence intensity of calcein in SME was signifi cantly higher than that of a calcein solution at all time points.

Moreover, the pilocarpine SME exhibited a longer duration of miosis than the simple pilocarpine solution. It should be mentioned that SMEs are true emulsions, being different from MEs. They do not form spontaneously and are kinetically rather than thermodynamically stable. They generally require high - shear homogenization to form and are more susceptible to phase inversion.

Furthermore, they are neither transparent nor translucent but rather turbid due their larger droplet size compared to MEs. While the two terms are used interchangeably in the the scientifi c literature, they actually refer to two distinct categories of dispersed systems and should be differentiated from each other.

The w/o MEs composed of water, Crodamol EO, Crill 1, and Crillet 4 were investigated as potential ocular delivery systems by Alany et al. It was hypothesized that w/o MEs undergo phase transition into lamellar liquid crystals (LCs) upon aqueous dilution by the tears, prolonging the precorneal retention time due to an increase in the formulation ’ s viscosity.

HET - CAM studies revealed no ocular irritancy by the excipients used. Ocular drainage was evaluated via γ - scintigraphy and demonstrated a signifi cantly higher precorneal retention of the tested microemulsions compared to an aqueous solution.

The use of MEs in ocular delivery is very attractive due to all the advantages offered by these formulations. They are thermodynamically stable and transparent, possess low viscosity, and thus are easy to instill, formulate, and sterilize (via fi ltration).

Moreover, they offer the possibility of reservoir and/or localizer effects. All these factors, in addition to the ones previously mentioned, render MEs promising ocular delivery systems.

Many other ocular delivery approaches have been investigated over the past decades, including the use of prodrugs, penetration enhancers, cyclodextrins, as well as different types of ocular inserts. In addition, iontophoresis, which is an active drug delivery approach utilizing electrical current of only 1 – 2 mA to transport ionized drugs across the cornea, offers an effective, noninvasive method for ocular delivery.

Another more recent approach is the use of dendrimers in ocular therapy. Dendrimers are synthetic spherical molecules named after their characteristic treelike branching around a central core with a size ranging from 2 to 10 nm in diameter. So far, PAMAM (polyamidoamine) has been the most commonly studied dendrimer system for ocular use.

Prodrugs

Prodrugs are pharmacologically inactive derivates of drug molecules that require a chemical or enzymatic transformation into their active parent drug. To be effective, an ocular prodrug should show an appropriate lipophilicity to facilitate corneal absorption, posses suffi cient aqueous solubility and stability to be formulated as an eye drop, and demonstrate the ability to be converted to the active parent drug at a rate that meets therapeutic needs.

When considering ophthalmic drug molecules as prodrug candidates, the following factors need to be considered: the pathway and mechanism of ocular drug penetration, the functional groups of the drug candidate amenable to prodrug derivatization, and the enzymes present in the ocular tissues, which are necessary for prodrug activation.

The majority of ophthalmic prodrugs developed so far are chemically classifi ed as ester. They are derived from the esterifi cation of the hydroxyl or carboxylic acid groups present in the parent molecule. Of all enzymes participating in the activation of prodrugs, esterases, which are present in all anterior segment tissues except the tear fi lm, have received the most attention.

However, the concept of prodrugs was not fully exploited until the introduction of dipivefrin (epinephrine prodrug) in the late 1970s. Kaback and co - workers found that a 0.1% dipivalyl epinephrine solution lowered the intraocular pressure as effective as a 2% epinephrine solution, while signifi cantly lowering the systemic side effects.

Wei et al. compared the ocular penetration, distribution, and metabolism of epinephrine and dipivalyl epinephrine and found the partition coeffi cient of the later to be 100 – 600 times higher than that of epinephrine, therefore leading to a 10 - times faster absorption into the rabbit eye.

Dipivefrin was the only commercially available ophthalmic prodrug at that time. However, numerous prodrug derivates have been designed to improve the effi cacy of ophthalmic drugs ever since.

Jarvinen and co - workers synthesized unique O, O′ - (xylylene)bispilocarpic acid esters containing two pilocarpic acid monoesters linked with one moiety. The found that prodrug showed a two - to seven - fold higher corneal permeability than pilocarpine itself despite the high molecular weight.

Tirucherai et al. formulated an acyl ester prodrug of ganciclovir. The increased permeability was associated with a linear increased susceptibility of the ganciclovir esters to the esterases present in the cornea.

So far, aims that have been achieved by using prodrugs include the modifi cation of the drug ’ s duration of action, reduction of the systemic absorption, and reduction of ocular and systemic side effects. Although prodrugs are commonly used to treat diseases of the anterior segment, there have also been attempts to treat conditions associated with the posterior segment of the eye.a

Penetration Enhancers

The transport process across the corneal tissue is the rate - limiting step in ocular drug absorption. Increasing the permeability of the corneal epithelium by penetration enhancers is likely to enhance the drug transport across the corneal tissues and therefore improve ocular bioavailability of the drug.

Penetration enhancers act by increasing the permeability of the corneal cell membrane and/or loosening the tight junctions between the epithelial cells, which primarily restrict the entry of molecules via the paracellular pathway. Classes of penetration enhancers include surfactants, bile salts, calcium chelators, preservatives, fatty acids, and some glycosides such a saponin.

Surfactants are perceived to enhance drug absorption by disturbing the integrity of the plasma membranes. When present at low concentrations, surfactants are incorporated into the lipid bilayer, leading to polar defects in the membrane, which change the membrane ’ s physical properties.

When the lipid bilayer is saturated, micelles start to form, enclosing phospholipids from the membranes, hence leading to membrane solubilization. Saettone et al. found an increased corneal permeability for atenolol, timolol, and betaxolol by including 0.05% Brij 35, Brij 78, and Brij 98 into their formulations.

Bile salts are amphiphilic molecules that are surface active and self - associate to form micelles in aqueous solution. They increase corneal permeability by changing the rheological properties of the bilayer. A number of bile salts such as deoxycholate, taurodeoxycholate, and glycocholate have been tested so far, and it was suggested, that a difference in their physicochemical properties (solubilizing activity, lipophilicity, Ca 2+ sequestration capacity) is probably related to their performance as permeability - enhancing agents.

Large numbers of penetration enhancers have been investigated to date. However, the unique structure of the corneal/conjunctival tissues requires caution. When selecting penetration enhancers for ocular delivery, their capacity to affect the integrity of the epithelial surfaces needs to be considered. Studies have shown that penetration enhancers themselves can penetrate ocular tissues, which could lead to potential toxicity.

EDTA concentrations in the iris – ciliary body, for example, were found to be high enough to alter the permeability of the blood vessels in the uveal tract, therefore indirectly accelerating the drug ’ s removal from the aqueous humor. Similarly, benzalkonium chloride (BAC), a cationic surfactant which shows the highest penetration - enhancing effect among the currently used preservatives, was found to accumulate in the cornea for several days.

Cyclodextrins

Cyclodextrins were introduced into the area of ocular drug delivery in the early 1990s. They are a group of homologous cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic cavity in the center. Their initial aim was to increase the solubility of lipophilic drugs by forming inclusion complexes.

Cyclodextrin complexation generally results in improved wettability, dissolution, solubility, and stability in solution as well as reduced side effects.

It is assumed that cyclodextrins are too large and hydrophilic to penetrate biological membranes. However, they act as penetration enhancers by assuring a high drug concentration at the corneal surface, from where the drug then partitions into the ocular tissues.

Even though cyclodextrins drug complexes seem to decrease ocular toxicity of irritant drugs, cyclodextrins themselves may exhibit ocular toxicity and should therefore be screened by performing corneal sensitivity studies. Among all cyclodextrin derivates investigated, hydroxy - propyl - β - cyclodextrin showed the most favorable properties in terms of toxicity.

Nijhawan and Agarwal investigated inclusion complexes of ciprofl oxacin hydrochloride and hydroxy - propyl - β - cyclodextrin and found that the complexes exhibited better stability, biological activity, and ocular tolerance than the uncomplexed drug in solution.

Aktas et al. showed an increased permeation of pilocarpine nitrate complexed with hydroxy - propyl - β - cyclodextrin using isolated rabbit cornea. They found a signifi cant reduction in the pupil diameter compared to a simple aqueous solution of the same active compound.

Cyclodextrins improve chemical stability, increase the drug

’ s bioavailability, and decrease local irritation. However, the improvement of ocular bioavailability seems to be limited by the very slow dissociation of the complexes in the precorneal tear fl uid.

Several studies have shown that combinations of cyclodextrins drug complexes and viscosity enhancers can signifi cantly improved ocular absorption and should therefore be further investigated.

Ocular Inserts

Solid ocular dosage forms such as fi lms, erodible and nonerodible inserts, rods, and shields have been developed to overcome the typical pulse - entry - type drug release associated with conventional ocular dosage forms. This pulse entry is characterized by a transient overdose, a relatively short period of appropriate dosing, followed by a prolonged period of underdosing.

Ocular inserts were developed in order to overcome these disadvantages by providing a more controlled, sustained, and continuous drug delivery by maintaining an effective drug concentration in the target tissues and yet minimizing the number of applications.

Ocular inserts probably represent one of the oldest ophthalmic formulation approaches. In 1948 the British Pharmacopoeia described an atropine - in – gelatin wafer and ever since then numerous systems have been developed applying various polymers and different release principals. However, the diffi culty of insertion by the patient, foreign - body sensation, and inadvertent loss of inserts from the eye make these systems less popular, especially among the elderly. Furthermore, the high cost involved in manufacture prevented the insert market from taking off.

Two products, Alza Ocusert and Merck Lacrisert, have been marketed, although Ocusert is no longer available. Ocusert is a membrane - controlled reservoir system for the treatment of glaucoma. It contains pilocarpine and alginic acid in the core reservoir, sandwiched between two transparent, lipophilic ethylenevinyl acetate (EVA) rate - controlling membranes, which allow the drug to diffuse from the reservoir at a precisely determined rate for a period of seven days.

This system is nonbiodegradable and must therefore be removed after use. Lacrisert, on the other hand, is a soluble minirod of hydroxypropylmethyl cellulose without any active ingredient.

The system is placed in the conjunctival sac, where it softens within an hour and completely dissolves within 14 – 18 h. Lacrisert stabilizes and thickens the precorneal tear fi lm and prolongs the tear fi lm break - up time, which is usually accelerated in patients with dry - eye syndrome (keratoconjunctivitis sicca).

A number of ocular inserts using different techniques,

namely soluble, erodible, nonerodible, and hydrogel inserts with polymers such as cellulose derivates, acrylates, and poly(ethylene oxide), have been investigated over the last few decades.

An example of a degradable matrix system is the pilocarpine - containing inserts formulated by Saettone et al. Pilocarpine nitrate and polyacrylic acid were incorporated into a matrix containing polyvinyl alcohol and two types of hydroxypropyl methylcellulose. It was shown that all inserts signifi cantly increased the pharmacological effect (miotic response) compared to a solution of pilocarpine nitrate.

Sasaki et al. prepared nondegradable disc - type ophthalmic inserts of β - blockers using different polymers. They found that inserts made from poly(hydroxypropyl methacrylate) were able to control the release of tilisolol hydrochloride.

Numerous studies have also been performed on soluble collagen shields. Collagen shields are fabricated from porcine scleral tissue, which has a similar collagen composition to that of the human cornea. Drug loading is typically achieved by soaking the collagen shield in the drug solution prior to application. Designed to slowly dissolve within 12, 24, or 72 h, collagen shields have attracted much interest as potential sustained ocular drug delivery systems over the last years.

Although conventional eye drops still represent about 90% of all marketed ophthalmic dosage forms, there have been signifi cant efforts towards the development of new drug delivery systems.

Only a few of these new ophthalmic drug delivery systems have been commercialized over the past decades, but research in the different areas of ocular drug delivery has provided important impetus and dynamism, with the promise of some new and exciting developments in the fi eld.

An ideal ophthalmic delivery system should be able to achieve an effective drug concentration at the target site for an extended period of time while minimizing systemic side effects. In addition, the system should be comfortable and easy to use, as the patient ’ s acceptance will continue to play an important role in the design of future ocular formulations.

All delivery technologies mentioned in this chapter hold unlimited potential for clinical ophthalmology. However, each of them still bears its own drawbacks. To circumvent these, newer trends are directed toward combinations of the different drug delivery approaches. Examples for this include the incorporation of particulates into in situ gelling systems or coating of nanoparticles with mucoadhesive polymers.

These combinations will open new directions for the improvement of ocular bioavailability, but they will also increase the complexity of the formulations, thus increasing the diffi culties in understanding the mechanism of action of the drug delivery systems.

Many interesting delivery approaches have been investigated during the past decades in order to optimize ocular bioavailability, but much remains to be learned before the perfect ocular drug delivery system can be developed.